ABSTRACT In 2013, more than 20,000 patients in the US were diagnosed with joint infection. Despite surgical intervention with debridement of necrotic tissue, aggressive lavage with antiseptic solutions, and systemic antibiotic treatment, the mortality rate exceeds 11% and recurrence is common. Furthermore, the aggressive treatments damage the joint ensuring later arthritis. Once bacteria access the joint capsule, our preliminary data suggest that bacterial contaminants become recalcitrant to antibiotic treatments due to formation of large bacterial aggregates that can be floating or loosely associated with tissues. We propose to develop new treatments that disrupt and prevent re-formation of bacterial aggregates in septic joints to allow effective antibacterial treatment. To attack this problem, we propose three specific aims: Specific Aim 1: To inhibit bacterial aggregate formation in synovial fluid through treatment with drugs that alter protein aggregation. We hypothesize that inhibition of aggregation will allow antibiotic access and increased effectiveness. Specific Aim 2: To permeabilize synovial fluid aggregates using ultrasound-mediated microbubble rupture in an ex vivo model of the joint. We hypothesize that microbubble cavitation will permeabilize aggregates to increase antibiotic efficacy towards bacteria within the clump. Specific Aim 3: To eradicate joint infection, in vivo, through combined microbubble/drug/antibiotic treatments. We will test the hypothesis that joint infections may be treated more effectively by the local application of microbubble cavitation in the presence of agents from Specific Aim 1 and amikacin. To attack this problem, we have assembled a team of experts in orthopaedic infection, animal models of disease, ultrasound physics, musculoskeletal disease together with a practicing orthopaedic surgeon specializing in joint infection. The success of our proposed approach will lead to higher treatment success rates, so that the pain, cost, suffering and mortality associated with joint infections will be markedly reduced.